ORIGINAL RESEARCH published: 01 October 2018 doi: 10.3389/fgene.2018.00424

Specificity: A Phenotypic Comparison of Communication-Relevant Domains Between Youth With Down Syndrome and Fragile X Syndrome

Laura del Hoyo Soriano 1,2*, Angela John Thurman 1,2 and Leonard Abbeduto 1,2

1 MIND Institute, University of California, Davis, Sacramento, CA, United States, 2 Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, CA, United States

Despite the shared presence of an intellectual disability (ID), there is a growing literature documenting important phenotypic differences between Down syndrome (DS) and fragile X syndrome (FXS). These conclusions, however, are based on a synthesis across studies, each of which typically includes only measures of a limited number of constructs, and with differing participant characteristics. Firmer conclusions regarding specific

Edited by: phenotypes require a single comprehensive multi-domain assessment of participants Manuel Mattheisen, with the syndrome groups being well matched on chronological age (CA) and cognitive Universitätsklinikum Würzburg, Germany functioning. The current study was designed to fill this gap by assessing several Reviewed by: important cognitive and behavioral domains relevant to communication, such as: Juko Ando, structural language skills, false belief understanding, as well as pragmatics and behavioral Keio University, Japan difficulties, in 30 adolescents of both sexes with DS and 39 males with FXS, matched on Baptiste Couvy-Duchesne, University of Queensland, Australia CA and nonverbal (NV) cognition. After statistically controlling for NV cognition, we did *Correspondence: not find significant syndrome differences in expressive and receptive structural language Laura del Hoyo Soriano or false belief understanding. In contrast, participants with DS displayed less stereotyped [email protected] language and fewer behavioral difficulties compared to males with FXS. Within-syndrome

Specialty section: associations among the targeted domains are described. Finally, females with DS This article was submitted to were less impaired than males with DS in almost all structural language domains, Behavioral and Psychiatric Genetics, whereas no significant sex-related differences were observed in NV cognition, false belief a section of the journal Frontiers in Genetics understanding, pragmatics, or behavior. Clinical and methodological implications of the

Received: 05 April 2018 findings are discussed. Accepted: 10 September 2018 Published: 01 October 2018 Keywords: Down syndrome, fragile X syndrome, phenotype, language, communication, false belief understanding, behavior Citation: del Hoyo Soriano L, Thurman AJ and Abbeduto L (2018) Specificity: A INTRODUCTION Phenotypic Comparison of Communication-Relevant Domains Down syndrome (DS) is typically caused by an extra copy of all or part of chromosome 21 Between Youth With Down Syndrome and Fragile X Syndrome. (Patterson, 2007). It is the most common known genetic cause of intellectual disability (ID) and, Front. Genet. 9:424. except in relatively infrequent cases of translocations, DS is not inherited (Grieco et al., 2015). doi: 10.3389/fgene.2018.00424 Fragile X syndrome (FXS)-the leading inherited cause of ID- is caused by the expansion of a CGG

Frontiers in Genetics | www.frontiersin.org 1 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS trinucleodide repeat located in the FMR1 gene on the long arm of Males with FXS also demonstrate structural language the X chromosome (Saldarriaga et al., 2014). Despite the presence production impairments relative to CA expectations. However, of an ID and, therefore, increased risk of communication findings are somewhat mixed as to whether their skills in this impairment in both conditions (Abbeduto and Hagerman, domain are more delayed than expected based on level of 1997; Foley et al., 2015), important phenotypic differences have cognitive functioning (Roberts et al., 2007a; Kover and Abbeduto, been observed between DS and FXS. For example, challenging 2010; Estigarribia et al., 2011). Some studies comparing males behavior and pragmatic (i.e., social) language problems appear to with FXS to cognitively matched typically developing (TD) be more common or severe in FXS, whereas structural language children, show expressive and receptive grammar and vocabulary deficits (e.g., syntactic), although present in FXS, are greater in consistent with mental age (MA) expectations (Abbeduto et al., DS (Abbeduto and Hagerman, 1997; Chapman and Hesketh, 2003; Price et al., 2007; Roberts et al., 2007d; Finestack and 2000; Abbeduto and Chapman, 2005; Abbeduto et al., 2007; Abbeduto, 2010). In contrast, other studies show significantly Finestack et al., 2009; Finestack and Abbeduto, 2010). Social- poorer structural language skills in males with FXS relative to cognitive impairments, which contribute to communicative younger TD children with similar NV MAs (Roberts et al., difficulties, seem to be comparable in degree across the two 2007a; Price et al., 2008; Martin et al., 2013). In addition, syndromes, although the types of errors made in social-cognitive conductive hearing loss associated with recurrent otitis media processing may be specific to each etiology (Abbeduto et al., 2001; is often observed in individuals with FXS and may contribute Cornish et al., 2005). to problems with the structural aspects of expressive language It is important to recognize, however, that most cross- (Barnes et al., 2009), just as in the case of DS (Stoel-Gammon, syndrome studies have assessed only a few domains of 2001). functioning and often have not controlled for other relevant Direct comparisons of structural language difficulties between differences between the syndromes, such as cognitive ability. DS and FXS have been relatively infrequent, and the findings Moreover, participant characteristics, such as chronological age inconsistent across studies. Some studies have not shown (CA) and sex, have differed across study samples. The current differences between the two conditions (Hogan-Brown et al., study was designed to fill the gaps in our knowledge of the 2013), whereas several other studies suggest that those with FXS syndrome-specific phenotypic profiles of DS and FXS, after have better syntactic skills, both receptively and expressively, than matching/controlling for CA and nonverbal (NV) cognition, by their cognitively matched peers with DS (Price et al., 2007, 2008; assessing several important cognitive and behavioral domains Finestack and Abbeduto, 2010). related to communication, including structural language, social Regarding social cognition, most of the studies performed cognition, pragmatic skills and behavioral difficulties in 30 in individuals with FXS or DS have generally focused on adolescents of both sexes with DS and 39 males with FXS. It is impairments in their Theory of Mind (ToM)—the “theory” that important to note that because FXS is an X-linked condition, other people have intentions, thoughts, beliefs and emotions, and females with FXS are, as a group, less severely affected than that these various epistemic states influence people’s behavior males (Hagerman et al., 1992). More specifically, although and how they interact with others, as well as an understanding there is a wide range of functioning observed, depending on that other people’s epistemic states can differ from one’s own the proportion of active cells that have the non-affected X (Carpendale et al., 2007). With regard to DS, there is paucity chromosome (Loesch et al., 2004; Ligsay and Hagerman, 2016), of research on ToM, perhaps reflecting the assumption that less than a third of females with FXS have an ID, making a children with DS have relatively strong social skills. However, comparison with females with DS (or even males with FXS) recent studies have shown that children and adolescents with DS difficult to interpret. Thus, females with FXS were excluded from exhibit problems relative to CA expectations with higher-order the present study. cognitive processing of social information affecting interpersonal Regarding language skills, there is considerable research understanding (Fidler, 2006; Cebula et al., 2010). documenting that structural language skills (i.e., syntax, In the case of those with FXS, it has been well documented that vocabulary, phonology) constitute one of the most impaired males with FXS are impaired relative to CA expectations with aspects of the cognitive profile of individuals with DS. Indeed, regard to ToM, having difficulties in differentiating appearance expressive syntax is especially impaired, with performance from reality (Cornish et al., 2005). In addition, males with co- lagging relative to both NV cognitive and vocabulary level- morbid FXS and autism spectrum disorder (ASD) have greater expectations (Finestack and Abbeduto, 2010; Channell et al., deficits than those with FXS alone (Lewis et al., 2006); however, 2015; Lee et al., 2017). At the same time, there is evidence of it has been suggested that both subgroups of FXS are superior as sex-related variability in structural language skills in the DS regards ToM performance to that of individuals with idiopathic population, with females displaying a longer mean length of ASD (Abbeduto and Murphy, 2004). utterance (MLU) in words, and using richer vocabulary and A cross-syndrome comparison study of males with DS and syntax than males from a very young age (Berglund et al., males with FXS (matched on verbal MA) (Cornish et al., 2001). Hearing loss and differences in oral-facial anatomy 2005) showed comparable difficulties between the groups in the and physiology also negatively impact speech perception and ability to understand beliefs and intentions, although qualitative production in both males and females with DS (Stoel-Gammon, differences in error types between the groups were observed. 2001), but with considerable within-syndrome variability in this Realist errors, ignoring the appearance of an object and instead regard (Karmiloff-Smith et al., 2016). relying solely on real knowledge, were more common in FXS,

Frontiers in Genetics | www.frontiersin.org 2 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS whereas participants with DS tended to demonstrate more conversational context vs. standardized methods) (Lee et al., phenomenist errors, relying on perceptual information about an 2017). object even if it contradicts real knowledge of that object. In When comparing pragmatic abilities in DS and FXS, several another study, it was found that a group of males with FXS, studies suggest that individuals with DS have fewer difficulties ranging in age from childhood to young adulthood, performed than males with FXS, at least with respect to the behavioral better on a false belief task assessing ToM than did a group and social-motivational components of pragmatic skills (Wolf- of individuals with DS who were CA- and NV MA-matched Schein et al., 1987; Sudhalter and Belser, 2001; Roberts et al., (Abbeduto et al., 2001). Note that differences in language skill 2007b). It’s unclear, however, the extent to which the higher did not fully explain the group differences in this latter study. rates of anxiety and ASD symptomatology observed in FXS In addition, some studies comparing DS and FXS to TD have relative to DS (Moss et al., 2013; Thurman et al., 2014; Niu reported asynchrony between false belief understanding and et al., 2017)—which are further detailed in the section below— cognitive level for adolescents with DS, but not for adolescents contribute to these patterns of between-group differences in with FXS (Abbeduto et al., 2001; Losh et al., 2012). However, pragmatics. However, males with FXS have been found to have when comparing FXS to other IDs of unknown etiology, a similar more complete knowledge of appropriate language for diverse asynchrony has been found in males with FXS (Grant et al., 2007). social situations than individuals with DS (Martin et al., 2013). Thus, findings about whether the understanding of false beliefs is Therefore, specific pragmatic deficits linked to each syndrome on par with cognitive level expectations are mixed for both DS may exist and are likely related to other aspects of their cognitive, and FXS. behavioral and social phenotypes (Martin et al., 2009; Estigarribia Regarding pragmatics, or the use of language to achieve et al., 2012). social ends, there is considerable evidence of performance below Regarding behavioral problems, individuals with FXS, cognitive level-expectations in males with FXS. In addition to especially males, generally display a variety of impairments delays in acquiring basic pragmatic skills (Abbeduto et al., 2007), that emerge early in childhood (Rivera and Reiss, 2009). These males with FXS also display atypical pragmatic behaviors. Most include hyperactivity, hyperarousal, and unusual or exaggerated notable in this regard is perseveration, or the excessive repetition responses to sensory stimuli, impulsivity, and inattention (Turk, of a word, phrase, or topic in conversation (Abbeduto and 1998; Munir et al., 2000; Cornish et al., 2007), aggression and Hagerman, 1997). Perseveration is more common in FXS than self-injury (Symons et al., 2003), social anxiety (Merenstein et al., in either males with DS or TD of similar MA (Abbeduto and 1996; Cordeiro et al., 2011), and ASD-like behaviors (Kau et al., Hagerman, 1997). Males with FXS also tend to produce more off- 2004; Clifford et al., 2007). Those ASD-like behaviors present in topic and tangential language than individuals with DS (Wolf- more than 90% of males with FXS (Feinstein and Reiss, 1998; Schein et al., 1987; Sudhalter et al., 1990; Roberts et al., 2007c). Bailey et al., 2000) include perseverative and noncontingent In addition, differences in narrative, or storytelling, skills, such as speech (Martin et al., 2012), motor stereotypies such as hand fewer story actions used in their narrative retellings, are observed flapping, and poor eye contact (Merenstein et al., 1996; Roberts for males with FXS relative to MA-matched TD individuals et al., 2007b; Oakes et al., 2016). (Estigarribia et al., 2011). In contrast, individuals with DS have been claimed to In contrast, youth with DS are generally thought to have display fewer behavioral problems than individuals with other a relative strength in pragmatic skills, at least in those skills ID conditions, including FXS (Tonge and Einfeld, 2003; Foley reflecting social motivation. Indeed, a recent set of studies et al., 2015). Nonetheless, some aspects of behavior are impaired conducted with children and adolescents with DS suggests compared to the general population (Næss et al., 2017). For relatively intact nonverbal communication skills (Smith et al., example, individuals with DS have trouble controlling impulses 2017), and rates of parent-reported social relationships and and managing frustration in late childhood and adolescence frequencies of attempts to repair conversational breakdown that (Merrick et al., 2004). This frustration may be related to are similar to TD MA-matched controls (Johnston and Stansfield, the barriers they experience due to the difficulties expressing 1997; Laws and Bishop, 2004). At the same time, however, themselves or understanding others (Chapman and Hesketh, other aspects of pragmatics are observed to be quite impaired 2000; Shapiro and Accardo, 2010). As individuals get older, in those with DS, including requesting (Coggins et al., 1983; those externalizing behaviors tend to decline, whereas increased Beeghly et al., 1990), topic initiation and elaboration (Tannock, internalizing symptoms (e.g., social withdrawal, depression, 1988; Roberts et al., 2007c), appropriately maintaining a topic anxiety, secretive behavior) are more likely to occur (Grieco of conversation (Tannock, 1988; Beeghly et al., 1990), providing et al., 2015). Finally, within DS, there is some, albeit inconsistent clear referential descriptions (Abbeduto et al., 2006), recognizing evidence, of sex differences with regard to behavioral difficulties; and requesting clarification of unclear messages (Abbeduto et al., indeed, some studies have suggested increased behavior problems 2008), use of stereotyped language (Laws and Bishop, 2004), in males (Van Gameren-Oosterom et al., 2011, 2013), whereas and understanding the contexts of conversation (Smith et al., others have reported increased problems in females (Dykens 2017), with performance below MA-expectations in several of et al., 2002), and still others have found no differences (Jacola these areas. In addition, sex-related differences in pragmatic et al., 2014). abilities in favor of females have been found in DS, although The inconsistency of the results across investigations targeting the extent of these differences varies as a function of CA, overall cognitive and behavioral skills may be due to several differences cognition, and methods of assessment (e.g., semi-naturalistic among studies, including differences in the CA and sex of the

Frontiers in Genetics | www.frontiersin.org 3 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS participants, the specific skills examined (e.g., different aspects METHODS of social-cognition, such as false belief understanding, joint attention, facial recognition), the methods used (e.g., naturalistic Participants tasks vs. standardized tasks, directly assessed vs. caregiver- Sixty-nine individuals between the ages of 10 and 16 years ≤ ± reported), the units of measure (e.g., growth scores, raw scores, with intellectual disability (NVIQ 70 5) were included in scaled scores), the context of assessment (e.g., conversation vs. the current study. We included 39 males with FXS and 30 narration or clinic vs. home), the domain or method by which participants with DS (20 males and 10 females). Because FXS groups are matched (e.g., matched on NV MA vs. matched is X-linked and females with the full mutation are far less on verbal MA) (Phillips et al., 2014). Virtually every study impaired than males, with less than one-third meeting criteria described in the foregoing review focused on measuring a single for an intellectual disability, females with FXS were excluded or limited set of skills or behavioral difficulties in a relatively from the current study. Participants were screened to ensure that narrow domain of functioning. Moreover, relatively few of (a) they used speech as the primary mode of communication, these studies directly compared appropriately matched groups (b) regularly used three-word or longer phrases, (c) were native of participants with DS or FXS specifically; instead, usually English speakers, and (d) had no major uncorrected physical comparing a sample of participants with a single syndrome or sensory impairments that would interfere with the ability to to a matched TD comparison group. Although such studies perform the tasks included in the research protocol. Hearing are useful, stronger conclusions regarding phenotypic features problems were directly assessed in both FXS and DS groups by specific to a syndrome requires a comprehensive multi-domain establishing pure tone thresholds and requiring a threshold of assessment of participants and with comparison of the two 30 dB or better in one ear. Parents gave their written informed syndrome groups matched, ideally, on CA and level of cognitive consent before their son or daughter participated. Descriptive Table 1 functioning or degree of intellectual disability. Matching on demographic and clinical data are presented in . The an indicator of overall cognitive level provides a benchmark present data are derived from the first annual assessment of against which skills likely to depend on cognitive ability, such the longitudinal study. The participants in the present study as structural language, can be judged as relatively strong or were part of a larger longitudinal study, which has generated weak across the syndromes (Abbeduto et al., 2016). Matching several previous publications. Several of the language measures on CA is useful for providing a benchmark against which to included in the present analyses have been included in other judge skills and behaviors, such as adaptive behavior and even published studies from the larger longitudinal project (Pierpont challenging behavior, that are highly dependent on generalized et al., 2011; Kover et al., 2012; McDuffie et al., 2012; Finestack experience in the world and linked to cultural demands (e.g., et al., 2013) however, none of these previous studies included entry into, or exit from, school) as well as behaviors judged to the entire battery of language, pragmatic, social-cognitive, and be inappropriate because they violate CA expectations, such as behavioral measures included in the present study, and previous fear of separation from a parent (Boer, 2006; Scattone et al., studies only focused on selected subsets of the cohort reported 2011). That said, matching youth with DS and males with FXS on on here (e.g., only FXS males, only the most verbally capable both (CA and cognitive level) is difficult, mainly because males individuals, or only individuals without a comorbid diagnosis of with FXS have, on average, higher IQs than same-CA youths autism spectrum disorder). with DS (Finestack et al., 2013; Kover et al., 2013; Channell et al., 2014). Thus, matching on both parameters may require Procedures and Measures a combination of equating through participant selection and Participants completed a test battery that was administered over statistical adjustment. the course of two (typically consecutive) days. In most cases, the The current study was designed as to provide a comprehensive entire battery was administered to any given participant by the comparative approach to examine syndrome-related phenotypes same examiner at any given annual assessment. All measures by assessing several communication-related domains— were administered by well-trained graduate-level research structural language, social cognition, pragmatics and behavioral assistants with extensive experience working with individuals difficulties—in a single integrated assessment of participants with developmental disabilities. The measures presented in this with DS and FXS. The groups were matched on CA through paper are only a subset of those comprised in the battery, participant selection and on NV cognition through statistical concretely those targeting domains relevant to communication adjustment. This approach made it possible to determine the skills. syndrome specificity regarding the assessed communication- related domains (1) by identifying differences and similarities Direct Assessments between the two syndromes as regards level of functioning Nonverbal cognition in each domain. (2) We also examined within-syndrome The Brief IQ subtests of the Leiter International Performance interrelationships between structural language skills, social Scale—Revised (Leiter-R; Roid and Miller, 1997) were cognition, pragmatic abilities, and behavioral problems in administered. The Leiter-R is a nonverbally administered each etiologic group. In addition, (3) we examined differences (i.e., pantomimed) assessment in which no verbal responses between males and females with DS in the domains of skill are required. The subtests comprising the Brief IQ are: Figure and behavior we assessed and the relationships among these Ground, Form Completion, Sequential Order, and Repeated domains. Patterns, with the former two domains reflecting skills in the

Frontiers in Genetics | www.frontiersin.org 4 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS

TABLE 1 | Sociodemographic characteristics and clinical parameters. comprehension of phrases and sentences of varying syntactic complexity, with items focused on word order, function words, Down syndrome Fragile X syndrome and grammatical inflections. Participants select the one picture (n = 30) (n = 39) from an array of four that matches the meaning of the utterance MEAN [SD (range)] spoken by the examiner. Items are presented in blocks of four, Age with all items in the block exemplifying the same syntactic 12.7 12.8 construct (e.g., the plural morpheme). The total number of blocks (1.8[10–16]) (1.8[10–16]) passed (i.e., all four items answered correctly) was used in the Leiter-R IQ present analyses. Expressive language was assessed using the Expressive 42.7 46.8 Vocabulary Test (EVT; Williams, 1997) and the Syntax [7(36–65)] [10(36–73)] Construction Test from the Comprehensive Assessment of Leiter-R GS Spoken Language (CASL; Carrow-Woolfolk, 1999). In the EVT, 462 466.9 expressive vocabulary knowledge is assessed using pictures and [7.4 (442–474)] [10 (446–490)] examiner prompts to solicit labels or synonyms. The CASL Sex Syntax Construction (CASL-SC) subtest requires generating 20 males 10 females 39 males sentences embodying a variety of targeted morphosyntactic rules. Bilingual Sentences are elicited by asking the participant to formulate a 1 1 word, phrase, or sentence that is semantically and grammatically Race compatible with a verbal stimulus and drawing. For both Caucasian 29 Caucasian 35 measures, we used raw scores (i.e., the number of items answered African American 0 African American 1 correctly) to avoid the floor effects observed in the standard Native 0 Native 1 scores. Asian 0 Asian 0 Expressive language abilities were also assessed in a Hispanic 1 Hispanic 1 conversational context following procedures developed by Other 0 Other 1 Abbeduto and colleagues (Abbeduto et al., 1995; Kover et al., Genetics 2012; Berry-Kravis et al., 2013). These procedures involve a set Full trisomy 25 Full mutation 21 of topics to be introduced as well as scripts for introducing and Partial trisomy 0 Premutation 0 following up on the topics, with the goal being to minimize Translocation 0 Mosaic 12 examiner talk, encourage participant talk, and obtain 10 min Mosaic 0 Cytogenetic 4 of conversation. Conversations were audio-recorded and later Unknown 5 Unknown 2 transcribed and analyzed using the Systematic Analysis of Language Transcripts (SALT; Miller and Chapman, 1999). Five SD, standard deviation; n, number of participants; IQ, intellectual quotient; GS, growth score. dependent measures were derived with the unit of analysis being the C-unit (i.e., an independent clause and its modifiers, which could include dependent clauses): talkativeness (number visualization domain and the latter two reflecting skill in the of C-units attempted per minute), unintelligibility (proportion of domain of fluid reasoning. Growth Scores (GS) were used as C-units that were partly or completely unintelligible), dysfluency the metric of NV cognitive functioning because of the floor (proportion of C-units that contained a verbal dysfluency, false effects observed for IQ (standard scores) for the DS group start, or filler), lexical diversity (number of different words in 50 (28.6% of the DS sample obtained the minimum score of 36 complete and intelligible units or the full sample if less than 50 and exhibited a significant absolute skewness index (>2). GS C-units), and syntactic complexity (mean length of utterance in are equal-interval scores, also known as derived rasch scores, morphemes, or MLU). See Kover et al. (2012) for details of the which are conceptually similar to age-equivalents and reflective transcription process. of absolute ability (as opposed to IQ, which is age referenced) and have a mean of approximately 500 for fifth graders. Social cognition We administered a slightly modified version of the false belief Structural language assessments task (FBT) developed by (Benson et al., 1993), which was Four standardized measures were administered. Receptive designed to assess aspects of ToM. In the task, two stories vocabulary was assessed using the Peabody Picture Vocabulary are read aloud and enacted with props. Each story concerns a Test, Third Edition (PPVT-III; Dunn and Dunn, 1997). In this character who believes that a desired object is hidden in one task, the participant selects the drawing from a four-drawing location, but the participant knows that the object is actually array that best matches the meaning of a word spoken by hidden in another location. At the conclusion of each story, the the examiner. The raw score (i.e., total number of correct participant is asked two test questions to determine whether he answers) was used in the present analyses. The Test for Reception or she can discriminate between his or her true belief about of Grammar, Second Edition (TROG-2; Bishop, 2003a) was the object’s location from the story character’s false belief about administered to evaluate receptive syntax. The TROG-2 assesses the object’s location. In addition to the test questions, control

Frontiers in Genetics | www.frontiersin.org 5 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS questions are asked, some of which are designed to determine they are particularly useful in cases in which different measures of whether the participant has processed, and can recall, critical the same constructs are scored using different scales not directly events in each story, and some of which are structurally similar comparable (Dunst and Hamby, 2012). We categorized each to the test questions, but contain no mental state language, difference as large (effect size differences larger than 1 pooled so as to determine whether the participant can manage the standard deviation (|d| > 1), substantial (|d| > 0.7), medium linguistic structure of the test questions. The two stories differed (|d| > 0.5), or small (|d| > 0.3). Less than 0.3 pooled standard in that one required reasoning about a character’s beliefs about deviation was considered as not meaningfully different. In these the world (first-order reasoning), whereas the other required comparisons, we designated FXS as the standard, which means reasoning about a character’s beliefs about yet another character’s that positive values in Cohen’s d correspond to higher scores in beliefs about the world (second-order reasoning). The order of the DS group, whereas negative values in Cohen’s d represent presentation of the two stories was random across participants. lower DS scores in comparison to the FXS group. Note that Our modifications of the Benson et al. task consisted of minor Leiter-R, FBT, PPVT, TROG, EVT, CASL-SC, ELS-Talkativeness, wording changes in the story and control questions, as well as ELS-Lexical Diversity, and ELS-Syntactic Complexity, as well as increased standardization of the story enactment. all subscales from CCC-2 assess skills, whereas ELS-Dysfluency, ELS-Unintelligibility, as well as all subscales from CBCL/6-18 Caregiver Report Measures assess difficulties. Biological mothers served as informants for all caregiver report We next conducted an ANOVA, comparing DS and FXS, measures. with separate analyses for each dependent variable, in order to Pragmatic skills were assessed through the Children’s adjust the ANOVAs p-values for multiple comparisons (method Communication Checklist (CCC-2), (Bishop, 2003b). The CCC- described below). Differences were considered to be statistically 2 is a 70-item questionnaire designed to obtain information about significant if the resulting p-values were less than 0.05 after children’s communication abilities and behaviors. In the present controlling for multiple comparisons. Because the groups were study, we only included data from the four subscales focused not matched on Leiter-R GS [Cohen’s d −0.55 [−1.04, −0.05], on pragmatic abilities (inappropriate initiation, stereotyped p-value < 0.5, (Kover and Atwoo, 2013)], we next examined language, use of context, and NV communication). We used group differences on the cognitive and behavioral variables after scaled scores for the present analyses, with a low score indicative controlling for differences in Leiter-R GS using an ANCOVA of a more severe pragmatic impairment. analysis. We included syndrome (DS and FXS) as a between- Behavioral problems were assessed through the Child participants factor and Leiter-R GS as a covariate. Differences Behavior Checklist, Ages 6–18 (CBCL/6–18) (Achenbach and were considered to be statistically significant if the resulting p- Rescorla, 2001). The CBCL/6–18 is comprised of 118 items value was less than 0.05 after controlling for conducting multiple regarding children’s competencies and behavioral/emotional ANCOVAs. problems. Caregivers rate their child for how true each item is We also compared males and females within the sample of now or within the past 6 months using the following scale: 0 participants with DS. Here we first relied on Cohen’s d method to = not true (as far as you know); 1 = somewhat or sometimes categorize the differences between males and females in terms of true; 2 = very true or often true. A number of different scales the magnitude of the effect sizes. We next conducted an ANOVA, and metrics are generated form the CBCL/6–18. We focused comparing males and females with DS, with separate analyses for only on those scales reflecting especially challenging areas for each dependent variable, in order to adjust the ANOVA p-values one or both of the syndromes of interest: Anxious/Depressed; for multiple comparisons (described below). Group differences Attention Problems; Social Problems; Thought Problems; and were considered to be statistically significant if the resulting p- Withdrawn/Depressed. We used T scores. Higher scores reflected value was less than 0.05 after controlling for conducting multiple greater problems. ANOVAs. Because males and females with DS were matched on age and NV cognition, there was no need to include either Statistical Analysis as a covariate. Therefore, ANCOVAs were not applied for the Descriptive statistics were computed for all variables. Cognitive, within-DS analyses. language, social-cognitive, and behavioral variables from direct To explore the within-syndrome associations among assessments in which more than 10% of the sample obtained the NV cognition, structural language skills, social-cognitive maximum or the minimum score, and/or exhibited a significant abilities, pragmatic skills, and behavioral problems, correlation absolute skewness index (>2) were categorized as having ceiling coefficients were calculated separately for each syndrome group. or floor effects. Pearson or Spearman coefficients were used depending on results We first compared the DS group (including both males and for each variable in the Shapiro-Wilk test of normality. When females) to the CA-matched group of males with FXS on each appropriate, partial correlations were computed to control for of the dependent variables. In order to quantify the magnitude of Leiter-R GS. In these analyses, correlations were considered to the differences between DS and FXS, Cohen’s effect size (“Cohen’s be statistically significant if the resulting p-value was less than d”), which is the difference of the means of two independent 0.05 after controlling for conducting multiple within-group samples divided by the pooled standard deviation was calculated, correlations (described below). along with the 95% confidence interval (Cohen, 1988). Because Because a large number of statistical comparisons were made, standardized Cohen’s d do not depend on the nature of the scores, we applied the False Discovery Rate (FDR) procedure (Benjamini

Frontiers in Genetics | www.frontiersin.org 6 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS and Hochberg, 1995) in each set of analyses in order to control structural language variables, NV communication on the CCC-2, for multiple comparisons. This procedure essentially controls for or and social problems on CBCL/6-18. Interestingly, inclusion of multiple comparisons by specifying the proportion of significant Leiter-R GS as covariate had no effect on the group differences in results that could be false positives in contrast to a procedure stereotyped language on the CCC-2 or on withdrawn behaviors such as the Bonferroni correction that controls for the number estimated means, anxious symptoms, or thought and attention of tests conducted within a family of tests. It should be noted problems (CBCL/6-18)—all of those differences were significant that the FDR approach is less conservative than is the Bonferroni following the application of the FDR (see Table 2). approach. Note that the FDR-adjusted p-values are presented as q-values in tables and text if remaining significant. In addition, Impact of Sex in DS Participants ≥ we have reported only moderate and strong correlations (r 0.4) Descriptive statistics, Cohen’s d, and confidence intervals (95% that were significant after controlling for multiple comparisons. CI) for the comparison of females with DS and males with All statistical analyses were performed using the statistical DS—matched on both CA and NV cognition—on each of the software packages SPSS (Version 18.0; SPSS Inc., Chicago, IL, dependent variables are presented in Table 3. Cohen’s d revealed USA) and R (Version 3.1.1; The R Foundation for Statistical large differences (d > 1) on nearly all measures of structural Computing, Vienna, Austria). language, with all differences reflecting better performance onthe part of the females with DS. The exceptions were talkativeness RESULTS and dysfluency in conversation, which were found to fall in the no significant differences category according to Cohen’s d. Descriptive Demographic and Clinical Data We also found that the Cohen’s d suggested that there were no of the Participants significant differences between males and females with DS on any Socio-demographic data and clinical descriptors of the DS and of the measures of social cognition, pragmatic skills, or behavioral FXS participants are provided in Table 1. problems.

Cognitive, Language, and Behavioral Intercorrelations Among Constructs in DS Performance in DS Participants Compared Participants and FXS Males to FXS Males We examined the associations between NV cognition (Leiter-R Descriptive statistics, Cohen’s d, and confidence intervals (95% GS) and the remaining variables (see Table 4), doing so separately CI) for the comparison of participants with DS to those for DS participants and FXS males. Results showed that Leiter- CA-matched males with FXS on the dependent variables are R GS was correlated with receptive and expressive grammar summarized in Table 2. Regarding structural language, the (TROG and CASL), as well as with receptive and expressive Cohen’s d indicated that there were substantial differences for vocabulary (PPVT and EVT), in both syndromes. In addition, the PPVT and CASL, and medium differences were observed NV cognition was associated with false belief understanding for the EVT, TROG, lexical diversity and syntactic complexity (FBT) and the conversational measures of dysfluency, syntactic in conversation, all with greater deficits in DS than FXS. complexity, and lexical diversity in the FXS group. No significant differences between groups were suggested by We also examined the associations between structural the Cohen’s d in the remaining conversation measures (i.e., language, pragmatic skills, false belief understanding and talkativeness, unintelligibility, and dysfluency). behavioral problems, doing so separately for each group. As With respect to social cognition, Cohen’s d suggested that regards the FXS group, results showed significant correlations there were no meaningful differences in the FBT. In reference between false belief understanding (FBT) and the following to the Cohen’s d for the pragmatic domains of the CCC- measures of structural language: expressive and receptive 2, substantial differences were found on stereotyped language vocabulary (EVT, PPVT) [(r = 0.62, p < 0.001, q = 0.005, CI and medium differences for both NV communication and =0.37, 0.786), (r = 0.60, p < 0.001, q = 0.005, CI = 0.343, 0.774)], inappropriate initiation, with greater parent-reported skill for and expressive and receptive grammar (TROG, CASL) [(r = 0.71, DS than FXS. Finally, Cohen’s d indicated that there was no p < 0.001, q = 0.005, CI = 0.501, 0.841), (r = 0.63, p < 0.001, q significant difference between groups for proper use of context on = 0.005, CI = 0.376, 0.796)]; however, none of these correlations the CCC-2. was significant after partialling out NV cognition. No significant Regarding the Cohen’s d analyses for the CBCL/6-18, intercorrelations were found between the remaining measures of large differences were observed for anxiety and attentional structural language, false belief understanding, pragmatics and problems, substantial differences for thought problems, and behavior (either before or after partialling out NV cognition) medium differences for withdrawn-depressed symptoms and for the FXS group. As regards the DS group, results showed social problems. In all cases, parents reported lesser concerns for significant correlations between talkativeness and nonverbal DS than FXS. communication (r = 0.65, p < 0.001, q = 0.035, CI = 0.351, The results for the ANCOVA in which the DS participants 0.829), as well as between dysfluency and stereotyped language were compared to the males with FXS are also reported (r = 0.62, p = 0.001, q = 0.035, CI = 0.306, 0.812); however, in Table 2. After controlling for Leiter-R GS, there were no none of these associations were significant after partialling out significant differences between DS and FXS on any of the NV cognition.

Frontiers in Genetics | www.frontiersin.org 7 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS b b b b b b b b b b b b b b b b b b b 0.23 3.70 4.26 3.85 1.99 2.87 3.29 85.04 12.45 55.05 11.66 12.46 16.80 82.80 62.31 63.27 60.31 66.52 65.90 hecklist, b b b b b b b b b b b b b b b b b b b PVT, Peabody ignificant results es larger than 1 pooled 465.12 value (the mean). Note: F DS FXS = ith DS compared to CA-matched males Covariate-adjusted Mean 0.001) 19.19 52.29 < 0.23 1.5 51.08 0.10 2.79 9.34 0.21 1.61 5.10 0.52 0.42 77.22 0.69 0.16 3.71 0.19 1.75 59.71 0.01(0.02) 8.19 5.32 0.01(0.01) 10.1 56.54 0.01(0.006) 12.20 58.69 0.01(0.006) 11.94 57.95 -value) < < 0.001( -value < < q p ( < 0.07] 0.59 0.29 3.37 0.26] 0.10 2.89 76.09 0.18] 0.32] 0.63] 0.07] 0.04] 0.33] 0.02] 0.54] 0.05] 0.06] − − − − − − − − − − − − 0.4, 0.57] 95% CI Adjusted for NV cognition 0.97,0.02] 0.66 0.2 0.20 0.59,0.42] 0.44 0.61 12.44 0.12,0.99] 0.31 1.06 15.81 0.33,0.69] 0.05(—) 3.9 25.10 0.80,0.23] 0.25 1.35 1.30 1.04, 1.09, 1.05, 1.25, 1.18, 1.34, 1.66, 1.10, 1.01, 1.33, 1.00, 1.56, − [0.12,1.17] 0.05(—) 3.8 3.77 − − − − − − − − − − − − − − − − − Cohen’s effect size. Large differences (effect size differenc [ [ a score; FBT, False Belief Task; TROG, Test for Reception of Grammar; P guage; ELS Expressive Language Sample; CCC-2, Children’s Communication C ise this symbol (—) is included as a sign of not passing the FDR criterion. S 0.001) [ 0.001) [ < < a -value) .089 [ Covariates appearing in the model are evaluated at Leiter-R GS q 0.001, 0.001, b 6 missing values < 0.29(0.3,–) [ < 0.48(0.06,–) [ 0.09(0.75,–) [ 6 0.52(0.038,–) [ 0.39(0.14,–) [ 0.18(0.48,–) [ − − − 0.69 (0.007, 0.02) [ − 0.65(0.016, 0.04) 0.55 (0.030, 0.046) [ 0.57 (0.023, 0.045) 0.76 (0.003, 0.012) 0.84 (0.001, 0.005) [ 0.59 (0.027, 0.045) [ 0.59 (0.026, 0.045) [ 0.53 (0.034, 0.049) [ 0.84 (0.001, 0.005) [ 0.3), 0.61(0.023, 0.045) [0.08, 1.13] 0.77 (0.005, 0.017) [0.23, 1.30] − -value, − − − − − − − − 1.06 ( > p -1.16 ( ( − 2 1 2 1 5 2 4 5 5 5 6 1 6 5 1 6 1 6 1 1 or NV cognition on dependent measures for males and females w 8 8 n s) Cohen’s-d 5 missing values„ 5 9 38 missing value, 4 0.5); Mild/small differences (|d| 1.12) 55–156 38 > 0.25(0.27) 0–1 37 3.33(2.33) 0–7 33 3.94(2.21) 0–8 33 4.22(1.49) 2.45–8.24 34 1.82(2.19) 0–8 33 2.73(1.51) 0–5 33 Mean (SD) Range (min-max) 12.77(3.52) 6.5–20.20 34 13.48(9.98) 0–36 35 11.97(8.84) 0–24.26 34 466.89(9.97) 446–490 37 56.49(19.48) 34–103 37 20.10(12.74) 1.54–44.62 34 89.85(30.57) 59–157 34 1 1 1 3 1 3 3 3 4 4 3 4 4 n 3 missing values, rences; CI, confidence interval; F, Fisher-Snedecor quotient; GS, growth 3 are bolded in the table. Syntax Construction Test from the Comprehensive Assessment of Spoken Lan ons according to FDR procedure, we only reported significant q-values, otherw 0.7); Medium differences (|d| > 2 missing values„ 2 , and confidence intervals (95% CI) and ANCOVA models adjusted f d Mean (SD) Range (min-max) 1 missing value, 1 1); Substantial differences (|d| > Descriptive analyses, Cohen’s q-values represent p-values after controlling forafter multiple controlling comparis for multiple comparisons according to FDR procedure Picture Vocabulary Test; EVT, Expressive Vocabulary Test; CASL-SC, CBCL, Child Behavior Checklist; standard deviation (|d| TABLE 2 | Groups:ChronologicalAge Down syndrome (males and females) 12.7(1.81) Fragile X syndrome (male 10–16 30 12.8(1.78) 10–16 39 0 NV, nonverbal; SD, standard deviation; n, number of participants; d, diffe NV Cognition Leiter-R GS 461.96 (7.4) 442–474 29 with FXS. Social Cognition False belief understanding (FBT) 0.14 (0.18) 0–0.75 29 Receptive Structural Language Receptive grammar (TROG) 2.4 (1.63) 0–6 30 4.07 (3.67) 0–15 3 Receptive vocabulary (PPVT) 64.93 (23.06) 8–107 30 86.13 (3 Expressive Structural Language Expressive vocabulary (EVT) 44.7 (13.5) 0–74 29 Talkativeness (ELS) 12.47 (3.46) 7–19.9 27 Syntax construction (CASL-SC) 6.31 (6.39) 0–26 29 Unintelligibility (ELS) 16 (11.84) 0–57 27 Dysfluency (ELS) 22.73 (16.5) 0.95–66 27 Lexical diversity (ELS) 72.29 (29.15) 0–123 27 Less stereotyped language 5.12 (2.26) 1–12 26 Anxioussymptoms 52.93(4.67) 50–67 30 60.89(8.22) 50–83 38 Pragmatic Skills (CCC-2) Less inappropriate initiation 5.27 (2.13) 2–9 26 Syntactic complexity (ELS) 3.42 (1.18) 1.84–5.89 27 Proper use of context 1.27 (1.51) 0–6 26 Socialproblems 59.56(4.56) 50–69 30 63(7.68) 51–83 38 NV communication 3.81 (1.83) 1– 8 26 Behavioral Problems (CBCL/6-18) Withdrawn behaviors 58.73 (6.54) 50–73 30 62.58 (8.07) 50–7 Thoughtproblems 60.1(7.42) 50–75 30 66.65(8.07) 50–77 38 Attention problems 58.06 (5.01) 51–73 30 65.65 (8.5) 50–92 3

Frontiers in Genetics | www.frontiersin.org 8 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS

TABLE 3 | Descriptive analyses, Cohen’s d, and confidence intervals (95% CI) for cognitive, linguistic, social-cognitive, and behavioral performance of males with DS compared to females with DS matched on CA and NV cognition.

Groups: Down syndrome (males) Down syndrome (females) Cohen’s-da 95% CI (p-value, q-value)

Mean (SD) Range (min-max) n Mean (SD) Range (min-max) n

ChronologicalAge 12.7(1.98) 10–16 20 12.7(1.5) 10–14 10 0.01 [−0.78, 0.79] NV Cognition Leiter-RGS 460.32(7.20) 442–474 191 465.1(7.11) 450–474 10 −0.66(0.1,–) [−0.14, 1.43] Social Cognition False belief understanding (FBT) 0.11 (0.14) 0–0.5 191 0.2(0.22) 0–0.75 10 −0.51(0.3,–) [−1.27, 0.28] Receptive Structural Language Receptive grammar (TROG) 2.05 (1.57) 0–6 20 3.10 (1.6) 1–5 10 −0.66(0.1,–) [−1.42, 0.13] Receptive vocabulary (PPVT) 59.40 (24.07) 8–98 20 76 (16.93) 43–107 10 −0.75(0.06,–) [−1.51, 0.49] Expressive Structural Language Expressive vocabulary (EVT) 40.11 (12.97) 0–72 191 53.4(10.1) 42–74 10 −1.10(0.009,0.034) [−1.88, −0.26] Syntax construction (CASL-SC) 3.79 (3.44) 0–16 191 11.1(8.03) 1–26 10 −1.35(0.002,0.013) [−2.15, −0.47] Talkativeness (ELS) 12.95 (3.57) 6.9–17.9 173 11.66(3.3) 7.5–17.6 10 0.37(0.4,–) [−0.43, 1.15] Unintelligibility (ELS) 20.44 (11.99) 8.57–57 173 8.42(6.97) 0–22.67 10 1.15(0.008,0.034) [0.28,1.95] Dysfluency(ELS) 21.27(17.87) 0.95–66 173 25.23(14.43) 1.12–53.71 10 −0.24(0.6,–) [−1.01, 0.55] Lexical diversity (ELS) 60.06 (21.91) 0–90 173 93.1(28.93) 36–123 10 −1.34(0.002,0.013) [−2.15, −0.44] Syntactic complexity (ELS) 2.87 (0.77) 1.84-4.32 173 4.35(1.2) 2.34–5.89 10 −1.55(0.001,0.013) [−2.39, −0.63] Pragmatic Skills (CCC-2) Less inappropriate initiation 5.53 (1.97) 2–8 173 4.78(2.44) 2–9 91 0.35(0.4,–) [−0.47, 1.53] Less stereotyped language 5.24 (2.41) 1–22 173 4.89(2.09) 3–8 91 0.15(0.7,–) [−0.66, 0.96] Proper use of context 1.35 (1.54) 0–6 173 1.11(1.54) 0–4 91 0.16(0.5,–) [−0.66, 0.96] NV communication 4 (2.12) 0–8 173 3.44(1.13) 2–5 91 0.30(0.2,–) [−0.52, 1.1] Behavioral Problems (CBCL) Withdrawn behaviors 59.9 (7.12) 50–73 20 56.4 (4.67) 50–63 10 0.54(0.2,–) [−0.24, 1.3] Anxioussymptoms 53.8(5.36) 50–67 20 51.2(2.15) 50–57 10 0.57(0.2,–) [−0.22, 1.32] Socialproblems 59.4(4.73) 50–69 20 59.9(4.43) 54–67 10 −0.11(0.8,–) [−0.86, 0.65] Thoughtproblems 59.7(7.95) 50–75 20 60.9(6.52) 51–73 10 −0.16(0.7,–) [−0.92, 0.6] Attention problems 57.7 (4.37) 51–64 20 58.8 (6.3) 52–73 10 −0.22(0.6,–) [−0.97, 0.55]

NV, nonverbal; SD, standard deviation, n, number of participants; d, differences; CI, confidence interval; GS, growth score; FBT, False Belief Task; TROG, Test for Reception of Grammar; PPVT, Peabody Picture Vocabulary Test; EVT, Expressive Vocabulary Test; CASL-SC, Syntax Construction Test from the Comprehensive Assessment of Spoken Language; ELS Expressive Language Sample; CCC-2, Children’s Communication Checklist; CBCL, Child Behavior Checklist; 11 missing value, 33 missing values; aCohen’s effect size. Large differences (effect size differences larger than 1 pooled standard deviation (|d| > 1); Substantial differences (|d| > 0.7); Medium differences (|d| > 0.5); Mild/small differences (|d| > 0.3). Note: q-values represent p-values after controlling for multiple comparisons according to FDR procedure. We only reported those q-values that were significant after controlling for FDR, otherwise this symbol (—) is included as a sign of not passing the FDR test. Significant results after controlling by FDR procedure are bolded in the table.

DISCUSSION a consequence of their lower level of NV cognition. Or put differently, when statistically matched on NV cognition, the two This study was designed to determine which communication- groups are equally impaired in terms of virtually all structural relevant skills and behaviors, including structural language, false language variables examined. belief understanding, pragmatics, and behavioral difficulties, The present findings regarding structural language contrast distinguish youth with DS from males with FXS and which with the findings of several previous investigations that have are shared by both conditions in terms of a similar degree suggested a weakness in expressive syntax for participants of impairment. We also examined the intercorrelations among with DS relative to participants with FXS, even when the domains separately for each syndrome group. In addition, sex- groups are matched on cognitive functioning (Price et al., 2007, related differences and similarities within youth with DS were 2008; Finestack and Abbeduto, 2010). Because the present explored. project utilized multiple measures of structural language, including syntax measured in a standardized test and in a Structural Language and False Belief structured naturalistic conversation and with similar results Understanding Differences across measures, the difference between our findings relative Our results indicated that the poorer structural language skills to other studies are not likely to be due to task or context of individuals with DS relative to those with FXS are likely (Kover et al., 2012; Martin et al., 2013). Instead, it is more likely

Frontiers in Genetics | www.frontiersin.org 9 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS

TABLE 4 | Correlations between NV cognition and the assessed domains in DS participants and in FXS males.

Pearson correlations: r (p-value, q-value) [95% CI]

DS group (males and females) FXS group (males) NV cognition (Leiter-R GS)

Social Cognition False belief understanding (FBT) — 0.61 (<0.001, 0.001) [0.356, 0.78] Receptive Structural Language Receptive grammar (TROG) 0.54(0.002,0.008)[0.216,0.757] 0.79(<0.001, 0.001) [0.626, 0.887] Receptive vocabulary (PPVT) 0.66 (<0.001,0.001)[0.387,0.827] 0.75(<0.001, 0.001) [0.563, 0.864] Expressive Structural Language Expressive vocabulary (EVT) 0.71 (<0.001,0.001)[0.458,0.856] 0.78(<0.001, 0.001) [0.61, 0.881] Syntax construction (CASL-SC) 0.55(0.003,0.011)[0.223,0.766] 0.79(<0.001, 0.001) [0.620, 0.889] Talkativeness (ELS) — — Unintelligibility (ELS) — — Dysfluency (ELS) — 0.42 (0.013, 0.04) [0.095, 0.664] Lexical diversity (ELS) — 0.55 (0.001, 0.004) [0.26, 0.749] Syntactic complexity (ELS) 0.45 (0.02, —) 0.62 (<0.001, 0.004) [0.357, 0.792] Pragmatic Skills (CCC-2) Less inappropriate initiation — — Less stereotyped language 0.42 (0.04, —) — Proper use of context — — NV communication — — Behavioral Problems (CBCL) Withdrawn behaviors — — Anxious symptoms — — Social problems — — Thought problems — — Attention problems — —

NV, nonverbal; GS, growth score; FBT, False Belief Task; TROG, Test for Reception of Grammar; PPVT, Peabody Picture Vocabulary Test; EVT, Expressive Vocabulary Test; CASL-SC, Syntax Construction Test from the Comprehensive Assessment of Spoken Language; ELS Expressive Language Sample; CCC-2, Children’s Communication Checklist; CBCL, Child Behavior Checklist; CI, confidence interval; r, Pearson correlation; p-value, two tailed significance; Q-value; represent p-values after controlling for multiple comparisons according to FDR procedure. Only are reported significant correlations, otherwise this symbol — is included as a sign of p > 0.05. Only are reported significant q-values, otherwise this symbol (—) is included as a sign of not passing the FDR test. Significant results after controlling for multiple comparisons according to FDR procedure are bolded in the table. that the difference between our findings and those of previous Finally, we found no significant group differences in absolute studies is due to differences in participant characteristics, level of performance on the false belief understanding task such as age, sex distributions, or language criteria for (before and after controlling for NV cognition). This is consistent enrollment. with findings from previous studies (e.g., Cornish et al., 2005). More generally, our results make the point that conclusions Future studies may include multiple tools of assessment targeting about the syndrome-specific profile of DS and FXS regarding different aspects of false belief understanding by conducting targeted structural language skills will broadly depend on the more in-depth qualitative analyses of errors as well as examining group-matching variables and covariates included in the models. other facets of ToM (e.g., recognizing emotions in other At the same time, it is important to exercise caution when people’s facial expressions) in order to better describe each interpreting the results of any matching strategy. In particular, phenotype. the fact that covarying NV cognition eliminates significant differences on structural language does not mean that the Pragmatic Skills Differences genetic anomalies of the syndromes are somehow not important As perceived by caregivers, participants with DS were found in producing these deficits. Instead, the interpretation is that to demonstrate significantly greater competence in pragmatic those genetic anomalies affect structural language at least partly skills than participants with FXS (e.g., better NV communication, through pervasive influences on cognition. In addition, future less inappropriate imitations in conversations, as well as less investigations should include other potential matching factors stereotyped language) before controlling for NV cognition. (e.g., verbal IQ, social anxiety, among others). Such matching However, the only group-difference that remained significant could further clarify the pathways through which the genetic after controlling for NV cognition was stereotyped language. anomalies lead to the linguistic phenotypes of the syndromes. It may be that these differences are enhanced by other unique

Frontiers in Genetics | www.frontiersin.org 10 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS aspects of the behavioral and social phenotype of each syndrome. Within-Syndrome Intercorrelations Among For example, relative strengths in social engagement, social Constructs orientation (Fidler et al., 2008), and prosocial responses (Kasari When examining intercorrelations among the different et al., 2003) might enable individuals with DS to learn and constructs within each syndrome, we found that NV cognition use NV skills to achieve communicative ends despite their was related to standardized outcomes of receptive and expressive limitations in structural language. In contrast, individuals with grammar and receptive and expressive vocabulary in both FXS, although wiling to engage in social interaction, display DS and FXS groups. NV cognition was also associated with high rates of sensory disorders, social anxiety, poor eye contact, conversational measures of dysfluency, lexical diversity and as well as other behavioral problems (Abbeduto and Chapman, syntactic complexity, as well as with greater false belief 2005; Saldarriaga et al., 2014), all of which may limit aspects understanding (social cognition), in the FXS group. These of pragmatic development and, perhaps, even lead them to results suggest that NV cognition may contribute to expressive atypical patterns of communication, including frequent use of and receptive structural language skills in both syndromes. stereotyped and repetitive language. Thus, the present results Indeed, no intercorrelations among the structural language, suggest that the pragmatic impairments associated with FXS are pragmatic skills, social cognitive, and behavioral measures not simply a consequence of their cognitive delay, but also are were significant after controlling for NV cognition, further reflective of their behavioral difficulties and difficulties with social reinforcing the importance of the latter domain for both DS and interaction. FXS. Behavioral Differences The results of the current study are consistent with previous studies in showing more severe behavioral difficulties in CONCLUSION males with FXS than in individuals with DS. Before and after controlling for NV cognition, males with FXS displayed A cognitive and behavioral profile of strengths and weaknesses more behavioral symptoms reflecting problems with anxiety, regarding communication skills emerged for the two groups withdrawal, disordered thought, and attention than the in this study. The inclusion of NV cognition as a covariate participants with DS. Thus, as was true for stereotyped language, showed that genetic differences across groups lead to several these behavioral challenges associated with FXS appear to significant differences in expressive and receptive language be syndrome specific, at least in their degree. Such findings and that were closely related to their cognitive impairments. suggest that the pathway from the FMR1 mutation to certain However, significant syndrome-related differences in stereotyped behavioral and pragmatic challenges is not solely through language and challenging behaviors favoring DS were irrespective cognition. of overall cognitive level. In addition, within the DS group, females demonstrated richer structural language skills than Cognitive and Behavioral Differences Between Males males, whereas no significant differences were shown in NV and Females With Down Syndrome cognition, social cognition, pragmatics or behavior. More Females with DS demonstrated an advantage relative to males generally, our findings can be used to develop intervention with DS (matched on age and level of ID) with respect to all plans, targeting areas of greatest impairments and exploiting measures of expressive structural language (except talkativeness differential associations between problem areas. For example, and dysfluency). These findings are consistent with other improved communication in DS, may require focusing on studies documenting a female advantage in language for DS structural language, whereas improved communication in FXS (Berglund et al., 2001; Dionne et al., 2003; de Sola et al., may require targeting behavioral difficulties as well as structural 2015). It is important to note, however, that our study shows language. At the same time it is important to note the importance significant sex-related differences only in structural expressive of considering the type of assessment (i.e., standardized or language; no significant sex-related differences were found in naturalistic) in which language is elicited for individuals receptive language, social cognition, pragmatics, or behavior. with intellectual disability. Our results suggest, consistent The existing literature has been mixed with regard to these with previous investigations (Kover et al., 2012), that each latter domains. Although several studies have pointed to sex- context of assessment requires concrete yet overlapping language differences in pragmatics, behavior, and communication skills demands, having implications for conclusions drawn about (Lund, 1988; Berglund et al., 2001; Määttä et al., 2006; Van language profiles and therefore targets selected for intervention Gameren-Oosterom et al., 2011; de Sola et al., 2015; Lee et al., plans. 2017), studies focused on the adolescent period specifically have Finally, we want to point that our findings may not generalize generally shown no sex differences with regard to pragmatics to other age periods. Indeed, the cognitive and behavioral (Martin et al., 2017) or behavior (Jacola et al., 2014). Taken pattern described for DS in the current study might differ together, these results suggest that sex differences in DS may dramatically at a later age as a consequence of their high risk vary as a function of chronological age and developmental of developing the neuropathology associated wi9th Alzheimer’s level and, perhaps, the context of assessment. However, Disease and the resulting dementia-like symptoms (Lott, 2012). confirming this hypothesis will require use of a longitudinal Therefore, life-span longitudinal studies comparing DS and FXS approach. are needed.

Frontiers in Genetics | www.frontiersin.org 11 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS

LIMITATIONS AND FUTURE DIRECTIONS of the University of California, Davis. Since all participants were minors with intellectual disability, parents of subjects gave Some limitations relevant to the interpretation of our findings written informed consent in accordance with the Declaration of exist. First, the statistical approach conducted when analyzing Helsinki. patterns of correlations across variables within each diagnostic group did not allow us to compare groups in this regard AUTHOR CONTRIBUTIONS since we did not test the differences in correlations. In other words: the fact that one correlation is significant and that LdH conceived and designed the analytical plan for this another not, does not necessary mean that the correlations study, analyzed the data, interpreted the results, and wrote the are statistically different from each other. However, it still manuscript. AT was responsible for constructing and validating provides interesting information within each diagnosis group all data sets, verifying the written description of the methods, and generates hypotheses for future research. Second, the small and assisting with interpretation of the statistical findings. LA sample size of each diagnostic group may contribute to low conceived the overall design of the larger study and protocol statistical power to detect links between domains. In addition, it from which the data for this study were drawn, oversaw should be noted that the FDR approach used is less conservative data collection, and contributed to the analytical plan for than the Bonferroni approach. Further, the results of this study this study. All authors reviewed, edited, and approved the are based on the comparison between syndromes at a single manuscript. point in time. Longitudinal studies are needed to understand syndrome-specific developmental patterns of structural language, FUNDING pragmatics and behavior. This might help identify developmental periods that are most optimal for intervention for each condition. This research was supported by grant R01HD024356 and by Finally, females with FXS were excluded from our analyses, which the MIND Institute Intellectual and Developmental Disabilities did not allow us to preserve sex-matching when comparing Research Center (U54 HD079125), both from the National phenotypes. As in most previous studies, we excluded females Institute of Child Health and Human Development. The project with FXS because of the relatively lower severity of impairment described was also supported by the National Center for compared to males. However, it is also true that females with FXS Advancing Translational Sciences (NCATS), National Institutes show a set of communication limitations (Sterling and Abbeduto, of Health (NIH), through grant UL1 TR000002. 2012) related to their extreme shyness and social anxiety. In addition, their attentional deficits further complicate their social ACKNOWLEDGMENTS interaction, being distracted, or forgetting pertinent information during a conversation. We are cognizant of this limitation and We thank the families who participated in this study and the plan to include females with FXS in future studies. In summary, many members of the laboratory who assisted with this project. although the current study give us interesting information about We want to thank Danielle J. Harvey for reviewing the statistical the cognitive and behavioral profile of school aged children with procedures carried out in this project during the peer review DS and FXS, further longitudinal studies with larger samples are revision of this manuscript. LdHS was granted with a travel award needed to confirm our results. to present a portion of the current work in the 2017 Trisomy 21 Research Society Conference. Enclosed the sites where this work ETHICS STATEMENT was performed: the MIND Institute (University of California Davis, Sacramento, CA, USA), Waisman Center (University of This study was carried out in accordance with the Wisconsin-Madison, Madison, WI, USA), and New York State recommendations of the UC Davis Clinical Committee B. Institute for Basic Research in Developmental Disabilities (Staten The protocol was approved by the Institutional Review Board Island, NY, USA).

REFERENCES disabilities. Int. Rev. Res. Dev. Disabil. 50, 71–118. doi: 10.1016/bs.irrdd.2016. 05.006 Abbeduto, L., Benson, G., Short, K., and Dolish, J. (1995). Effects of sampling Abbeduto, L., Murphy, M., Cawthon, S., Richmond, E. K., Weissman, M. context on the expressive language of children and adolescents with mental D., Karadottir, S., et al. (2003). Receptive language skills of adolescents retardation. Mental Retard. 33, 279–288. and young adults with down or fragile X syndrome. Am. J. Mental Abbeduto, L., and Chapman, R. (2005). “Language and communication skills in Retard. 149, 149–160. doi: 10.1352/0895-8017(2003)108<0149:RLSOAA> children with down syndrome and fragile, x,”in Trends in Language Acquisition 2.0.CO;2 Research, Vol. 4 Developmental Theory and Language Disorders, eds P. Fletcher Abbeduto, L., and Murphy, M. M. (2004). Developmental Language Disorders. and J Miller (Amsterdam: John Benjamins), 53–57. Developmental Language Disorders: From Phenotypes to Etiologies. Abbeduto, L., and Hagerman, R. (1997). Language and communication in fragile Mahwah, NJ: Routledge. X syndrome. Mental Retard. Dev. Disabil. Res. Rev. 3, 313–322. doi: 10.1002/ Abbeduto, L., Murphy, M. M., Kover, S. T., Giles, N. D., Karadottir, S., Amman, A., (SICI)1098-2779(1997)3:4<313::AID-MRDD6>3.0.CO;2-O et al. (2008). Signaling noncomprehension of language: a comparison of Fragile Abbeduto, L., McDuffie, A., Thurman, A. J., and Kover, S. T. (2016). X syndrome and Down syndrome. Am. J. Mental Retard. 113, 214–230. doi: 10. Language development in individuals with intellectual and developmental 1352/0895-8017(2008)113[214:SNOLAC]2.0.CO;2

Frontiers in Genetics | www.frontiersin.org 12 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS

Abbeduto, L., Murphy, M. M., Richmond, E. K., Amman, A., Beth, P., Weissman, X full mutation and premutation. J. Autism Dev. Disord. 37, 738–747. M. D., et al. (2006). Collaboration in referential communication: comparison of doi: 10.1007/s10803-006-0205-z youth with Down syndrome or Fragile X syndrome. Am. J. Mental Retard. 111, Coggins, T. E., Carpenter, R. L., and Owings, N. O. (1983). Examining early 170–183. doi: 10.1352/0895-8017(2006)111[170:CIRCCO]2.0.CO;2 intentional communication in Down’s syndrome and nonretarded children. Br. Abbeduto, L., Pavetto, M., Kesin, E., Weissman, M. D., Karadottir, S., O’Brien, A., J. Disord. Commun. 18, 98–106. et al. (2001). The linguistic and cognitive profile of down syndrome: evidence Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences. from a comparison with fragile X syndrome. Down’s Syndr. Res. Pract. 7, 9–15. New York, NY: Routledge Academic. doi: 10.3104/reports.109 Cordeiro, L., Ballinger, E., Hagerman, R., and Hessl, D. (2011). Clinical Abbeduto, L., Warren, S. F., and Conners, F. A. (2007). Language development assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and in Down syndrome: from the prelinguistic period to the acquisition of characterization. J. Neurodev. Disord. 3, 57–67. doi: 10.1007/s11689-010-9067-y literacy. Mental Retard. Dev. Disabil. Res. Rev. 13, 247–261. doi: 10.1002/mrdd. Cornish, K., Burack, J. A., Rahman, A., Munir, F., Russo, N., and Grant, C. (2005). 20158 Theory of mind deficits in children with fragile X syndrome. J. Intellect. Disabil. Achenbach, T. M., and Rescorla, L. A. (2001). Manual for the ASEBA School-Age Res. 49, 372–378. doi: 10.1111/j.1365-2788.2005.00678.x Forms and Profiles. Burlington, VT: University of Vermont, Research Center Cornish, K., Scerif, G., and Karmiloff-Smith, A. (2007). Tracing syndrome- for Children, Youth, and Families. specific trajectories of attention across the lifespan. Cortex 43, 672–685. Bailey, D. B., Hatton, D. D., Mesibov, G., Ament, N., and Skinner, M. (2000). Early doi: 10.1016/S0010-9452(08)70497-0 development, temperament, and functional impairment in autism and fragile de Sola, S., de la Torre, R., Sánchez-Benavides, G., Benejam, B., Cuenca-Royo, X syndrome. J. Autism Dev. Disord. 30, 49–59. doi: 10.1023/A:1005412111706 A., Del Hoyo, L., et al. (2015). A new cognitive evaluation battery for Barnes, E., Roberts, J., Long, S. H., Martin, G. E., Berni, M. C., Mandulak, K. C., Down syndrome and its relevance for clinical trials. Front. Psychol. 6:708. et al. (2009). Phonological accuracy and intelligibility in connected speech of doi: 10.3389/fpsyg.2015.00708 boys with Fragile X syndrome or Down syndrome. J. Speech Lang. Hear. Res. Dionne, G., Dale, P. S., Boivin, M., and Plomin, R. (2003). Genetic evidence for 52, 1048–1061. doi: 10.1044/1092-4388(2009/08-0001) bidirectional effects of early lexical and grammatical development. Child Dev. Beeghly, M., Weiss-Perry, B., and Cicchetti, D. (1990). “Beyond sensorimotor 74, 394–412. doi: 10.1111/1467-8624.7402005 functioning: early communicative and play development of children with Dunn, L., and Dunn, L. (1997). Peabody Picture Vocabulary Test, 3rd Edn. Circle Down syndrome: a developmental perspective,” in Children with Down Pines, MN: American Guidance Service. syndrome: A Developmental Perspective, eds D. Cicchetti and M. Beeghly Dunst, C. J., and Hamby, D. W. (2012). Guide for calculating and (New York, NY: Cambridge University Press), 329–368. interpreting effect sizes and confidence intervals in intellectual and Benjamini, Y., and Hochberg, Y. (1995). Controlling the false discovery rate: a developmental disability research studies. J. Intellect. Dev. Disabil. 37, practical and powerful approach to multiple testing. J. R. Stat. Soc. Series B 57, 89–99. doi: 10.3109/13668250.2012.673575 289–300. Dykens, E. M., Shah, B., Sagun, J., Beck, T., and King, B. H. (2002). Maladaptive Benson, G., Abbeduto, L., Short, K., Nuccio, J. B., and Maas, F. (1993). behaviour in children and adolescents with Down’s syndrome. J. Intellect. Development of a theory of mind in individuals with mental retardation. Am. Disabil. Res. 46(Pt 6), 484–492. doi: 10.1046/j.1365-2788.2002.00431.x J. Mental Retard. 98, 427–433. Estigarribia, B., Martin, G. E., and Roberts, J. E. (2012). Cognitive, environmental, Berglund, E., Eriksson, M., Johansson, I., Nadel, L., Bates, E., Hartung, and linguistic predictors of syntax in fragile X syndrome and down syndrome. J. J. P., et al. (2001). Parental reports of spoken language skills in Speech Lang. Hear. Res. 55, 1600–1612. doi: 10.1044/1092-4388(2012/10-0153) children with down syndrome. J. Speech Lang. Hear. Res. 44, 179–191. Estigarribia, B., Roberts, J. E., Sideris, J., and Price, J. (2011). Expressive doi: 10.1044/1092-4388(2001/016) morphosyntax in boys with Fragile X syndrome with and without Berry-Kravis, E., Doll, E., Sterling, A., Kover, S. T., Schroeder, S. M., Mathur, autism spectrum disorder. Int. J. Lang. Commun. Disord. 46, 216–230. S., et al. (2013). Development of an expressive language sampling procedure doi: 10.3109/13682822.2010.487885 in Fragile X syndrome: a pilot study. J. Dev. Behav. Pediatr. 34, 245–251. Feinstein, C., and Reiss, A. L. (1998). Autism: the point of view from fragile X doi: 10.1097/DBP.0b013e31828742fc studies. J. Autism Dev. Disord. 28, 393–405. doi: 10.1023/A:1026000404855 Bishop, D. (2003a). Test for Reception of Grammar, Version 2. London: Fidler, D. (2006). The emergence of a syndrome-specific personality profile in Psychological Corporation. young children with Down syndrome. Down Synd. Res. Pract. 10, 53–60. Bishop, D. (2003b). The Children’s Communication Checklist, Version 2 (CCC-2). doi: 10.3104/reprints.305 London: Psychological Corporation. Fidler, D. J., Most, D. E., Booth-LaForce, C., and Kelly, J. F. (2008). Emerging Boer, H. (2006). International Handbook of Applied Research in Intellectual social strengths in young children with down syndrome. Infants Young Child. Disabilities. Edited by Eric Emerson, Chris Hatton, Travis Thompson & Trevor 21, 207–220. doi: 10.1097/01.IYC.0000324550.39446.1f R. Parmenter. Chichester: John Wiley & Sons. 2004. 656 pp. £100.00 (hb). ISBN Finestack, L. H., and Abbeduto, L. (2010). Expressive language profiles of 0471497096. Br. J. Psychiatry 188:496. doi: 10.1192/bjp.188.5.496 verbally expressive adolescents and young adults with Down syndrome Carpendale, J., Lewis, C., and Martin, J. (2007). How children develop social or fragile X syndrome. J. Speech Lang. Hear. Res. 53, 1334–1348. understanding. Can. Psychol. 48, 49–51. doi: 10.1037/cp2007_1_49 doi: 10.1044/1092-4388(2010/09-0125) Carrow-Woolfolk, E. (1999). Comprehensive Assessment of Spoken Language. Finestack, L. H., Richmond, E. K., and Abbeduto, L. (2009). Language development Circle Pines, MN: American Guidance Service. in individuals with fragile x syndrome. Topics Lang. Disord. 29, 133–148. Cebula, K. R., Moore, D. G., and Wishart, J. G. (2010). Social cognition in children doi: 10.1097/TLD.0b013e3181a72016 with Down’s syndrome: challenges to research and theory building. J. Intellect. Finestack, L. H., Sterling, A. M., and Abbeduto, L. (2013). Discriminating down Disabil. Res. 54, 113–134. doi: 10.1111/j.1365-2788.2009.01215.x syndrome and fragile X syndrome based on language ability. J. Child Lang. 40, Channell, M. M., McDuffie, A. S., Bullard, L. M., and Abbeduto, L. (2015). 244–265. doi: 10.1017/S0305000912000207 Narrative language competence in children and adolescents with Down Foley, K. R., Bourke, J., Einfeld, S. L., Tonge, B. J., Jacoby, P., and Leonard, syndrome. Front. Behav. Neurosci. 9:283. doi: 10.3389/fnbeh.2015.00283 H. (2015). Patterns of depressive symptoms and social relating behaviors Channell, M. M., Thurman, A. J., Kover, S. T., and Abbeduto, L. (2014). Patterns of differ over time from other behavioral domains for young people with Down change in nonverbal cognition in adolescents with Down syndrome. Res. Dev. syndrome. Medicine 94:e710. doi: 10.1097/MD.0000000000000710 Disabil. 35, 2933–2941. doi: 10.1016/j.ridd.2014.07.014 Grant, C. M., Apperly, I., and Oliver, C. (2007). Is theory of mind understanding Chapman, R. S., and Hesketh, L. J. (2000). Behavioral phenotype of individuals impaired in males with fragile X syndrome? J. Abnorm. Child Psychol. 35, 17–28. with Down syndrome. Mental Retard. Dev. Disabil. Res. Rev. 6, 84–95. doi: 10. doi: 10.1007/s10802-006-9077-0 1002/1098-2779(2000)6:2<84::AID-MRDD2>3.0.CO;2-P Grieco, J., Pulsifer, M., Seligsohn, K., Skotko, B., and Schwartz, A. (2015). Down Clifford, S., Dissanayake, C., Bui, Q. M., Huggins, R., Taylor, A. K., and Loesch, syndrome: cognitive and behavioral functioning across the lifespan. Am. J. Med. D. Z. (2007). Autism spectrum phenotype in males and females with fragile Genet. Part C. 169, 135–149. doi: 10.1002/ajmg.c.31439

Frontiers in Genetics | www.frontiersin.org 13 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS

Hagerman, R. J., Jackson, C., Amiri, K., Silverman, A. C., O’Connor, R., and Martin, G. E., Klusek, J., Estigarribia, B., and Roberts, J. E. (2009). Language Sobesky, W. (1992). Girls with fragile X syndrome: physical and neurocognitive characteristics of individuals with down syndrome. Topics Lang. Disord. 29, status and outcome. Pediatrics 89, 395–400. 112–132. doi: 10.1097/TLD.0b013e3181a71fe1 Hogan-Brown, A. L., Losh, M., Martin, G. E., and Mueffelmann, D. J. (2013). An Martin, G. E., Losh, M., Estigarribia, B., Sideris, J., and Roberts, J. (2013). investigation of narrative ability in boys with autism and fragile X syndrome. Longitudinal profiles of expressive vocabulary, syntax and pragmatic language Am. J. Intellect. Dev. Disabil. 118, 77–94. doi: 10.1352/1944-7558-118.2.77 in boys with fragile X syndrome or Down syndrome. Int. J. Lang. Commun. Jacola, L. M., Hickey, F., Howe, S. R., Esbensen, A., and Shear, P. K. (2014). Disord. 48, 432–443. doi: 10.1111/1460-6984.12019 Behavior and adaptive functioning in adolescents with Down syndrome: Martin, G. E., Roberts, J. E., Helm-Estabrooks, N., Sideris, J., Vanderbilt, J., specifying targets for intervention HHS Public Access. J. Ment. Health Res. and Moskowitz, L. (2012). Perseveration in the connected speech of boys Intellect. Disabil. 7, 287–305. doi: 10.1080/19315864.2014.920941 with Fragile X syndrome with and without autism spectrum disorder. Am. J. Johnston, F., and Stansfield, J. (1997). Expressive pragmatic skills in pre-school Intellect. Dev. Disabil. 117, 384–399. doi: 10.1352/1944-7558-117.5.384 children with and without Down’s syndrome: parental perceptions. J. Intellect. McDuffie, A., Kover, S., Abbeduto, L., Lewis, P., and Brown, T. (2012). Disabil. Res. 41(Pt 1), 19–29. Profiles of receptive and expressive language abilities in boys with comorbid Karmiloff-Smith, A., Al-Janabi, T., D’Souza, H., Groet, J., Massand, E., Mok, K., fragile x syndrome and autism. Am. J. Intellect. Dev. Disabil. 117, 18–32. et al. (2016). The importance of understanding individual differences in Down doi: 10.1352/1944-7558-117.1.18 syndrome. F1000Research 5:389. doi: 10.12688/f1000research.7506.1 Merenstein, S. A., Sobesky, W. E., Taylor, A. K., Riddle, J. E., Tran, H. X., Kasari, C., Freeman, S. F., and Bass, W. (2003). Empathy and response to distress and Hagerman, R. J. (1996). Molecular-clinical correlations in males with an in children with Down syndrome. J. Child Psychol. Psychiatry Allied Disciplines expanded FMR1 mutation. Am. J. Med. Genet. Part A 64, 388–394. 44, 424–431. doi: 10.1111/1469-7610.00132 Merrick, J., Kandel, I., and Vardi, G. (2004). Adolescents with Down syndrome. Kau, A. S., Tierney, E., Bukelis, I., Stump, M. H., Kates, W. R., Trescher, Int. J. Adoles. Med. Health 16, 13–19. doi: 10.1515/IJAMH.2004.16.1.13 W. H., et al. (2004). Social behavior profile in young males with fragile X Miller, J., and Chapman, R. (1999). SALT: Computer Program for the Systematic syndrome: characteristics and specificity. Am. J. Med. Genet. 126A, 9–17. Analysis of Language Transcripts. doi: 10.1002/ajmg.a.20218 Moss, J., Richards, C., Nelson, L., and Oliver, C. (2013). Prevalence of Kover, S. T., and Abbeduto, L. (2010). Expressive language in male adolescents with autism spectrum disorder symptomatology and related behavioural fragile X syndrome with and without comorbid autism. J. Intellect. Disabil. Res. characteristics in individuals with Down syndrome. Autism 17, 390–404. 54, 246–265. doi: 10.1111/j.1365-2788.2010.01255.x doi: 10.1177/1362361312442790 Kover, S. T., and Atwoo, A. K. (2013). Establishing equivalence: methodological Munir, F., Cornish, K. M., and Wilding, J. (2000). A neuropsychological profile of progress in group-matching design and analysis. Am. J. Intellect. Dev. Disabil. attention deficits in young males with fragile X syndrome. Neuropsychologia 38, 118, 3–15. doi: 10.1352/1944-7558-118.1.3 1261–1270. doi: 10.1016/S0028-3932(00)00036-1 Kover, S. T., McDuffie, A., Abbeduto, L., and Brown, W. T. (2012). Effects of Næss, K. B., Nygaard, E., Ostad, J., Dolva, A. S., and Lyster, S. A. H. (2017). The sampling context on spontaneous expressive language in males with fragile profile of social functioning in children with Down syndrome. Disabil. Rehabil. X syndrome or Down syndrome. J. Speech Lang. Hear. Res. 55, 1022–1038. 39, 1320–1331. doi: 10.1080/09638288.2016.1194901 doi: 10.1044/1092-4388(2011/11-0075) Niu, M., Han, Y., Dy, A. B. C., Du, J., Jin, H., Qin, J., et al. (2017). Kover, S. T., Pierpont, E. I., Kim, J. S., Brown, W. T., and Abbeduto, L. (2013). Autism symptoms in Fragile X syndrome. J. Child Neurol. 32, 903–909. A neurodevelopmental perspective on the acquisition of nonverbal cognitive doi: 10.1177/0883073817712875 skills in adolescents with fragile X syndrome. Dev. Neuropsychol. 38, 445–460. Oakes, A., Thurman, A. J., McDuffie, A., Bullard, L. M., Hagerman, R. J., and doi: 10.1080/87565641.2013.820305 Abbeduto, L. (2016). Characterising repetitive behaviours in young boys with Laws, G., and Bishop, D. (2004). Pragmatic language impairment and social fragile X syndrome. J. Intellect. Disabil. Res. 60, 54–67. doi: 10.1111/jir.12234 deficits in Williams syndrome: a comparison with Down’s syndrome and Patterson, D. (2007). Genetic mechanisms involved in the phenotype of specific language impairment. Int. J. Lang. Commun. Disord. 39, 45–64. Down syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 13, 199–206. doi: 10.1080/13682820310001615797 doi: 10.1002/mrdd.20162 Lee, M., Bush, L., Martin, G. E., Barstein, J., Maltman, N., Klusek, J., Phillips, B. A., Loveall, S. J., Channell, M. M., and Conners, F. A. (2014). Matching et al. (2017). A multi-method investigation of pragmatic development in variables for research involving youth with Down syndrome: Leiter-R versus individuals with down syndrome. Am. J. Intellect. Dev. Disabil. 122, 289–309. PPVT-4. Res. Dev. Disabil. 35, 429–438. doi: 10.1016/j.ridd.2013.11.016 doi: 10.1352/1944-7558-122.4.289 Pierpont, E. I., Richmond, E. K., Abbeduto, L., Kover, S. T., and Brown, W. T. Lewis, P., Abbeduto, L., Murphy, M., Richmond, E., Giles, N., Bruno, L., et al. (2011). Contributions of phonological and verbal working memory to language (2006). Cognitive, language and social-cognitive skills of individuals with fragile development in adolescents with fragile X syndrome. J. Neurodev. Disord. 3, X syndrome with and without autism. J. Intellect. Disabil. Res. 50, 532–545. 335–347. doi: 10.1007/s11689-011-9095-2 doi: 10.1111/j.1365-2788.2006.00803.x Price, J., Roberts, J., Vandergrift, N., and Martin, G. (2007). Language Ligsay, A., and Hagerman, R. J. (2016). Review of targeted treatments in fragile X comprehension in boys with fragile X syndrome and boys with syndrome. Intract. Rare Dis. Res. 5, 158–167. doi: 10.5582/irdr.2016.01045 Down syndrome. J. Intellect. Disabil. Res. 51(Pt 4), 318–326. Loesch, D. Z., Huggins, R. M., and Hagerman, R. J. (2004). Phenotypic variation doi: 10.1111/j.1365-2788.2006.00881.x and FMRP levels in fragile X. Ment. Retard. Dev. Disabil. Res. Rev. 10, 31–41. Price, J. R., Roberts, J. E., Hennon, E. A., Berni, M. C., Anderson, K. L., and doi: 10.1002/mrdd.20006 Sideris, J. (2008). Syntactic complexity during conversation of boys with Losh, M., Martin, G. E., Klusek, J., Hogan-Brown, A. L., and Sideris, J. (2012). fragile X syndrome and down syndrome. J. Speech Lang. Hear. Res. 51, 3–15. Social communication and theory of mind in boys with autism and fragile X doi: 10.1044/1092-4388(2008/001) syndrome. Front. Psychol. 3:266. doi: 10.3389/fpsyg.2012.00266 Rivera, S. M., and Reiss, A. L. (2009). “From genes to brain to behavior: the case of Lott, I. (2012). Neurological phenotypes for Down syndrome across the life span. fragile X syndrome,” in Neuroimaging in Developmental Clinical Neuroscience, Progr. Brain Res. 197, 101–121. doi: 10.1016/B978-0-444-54299-1.00006-6 eds J. M. Rumsey and M. Ernst (Bethesda, MD: Cambridge University Press), Lund, J. (1988). Psychiatric aspects of Down’s syndrome. Acta Psychiatri. Scand. p. 218–229. 78, 369–374. Roberts, J., Martin, G. E., Moskowitz, L., Harris, A. A., Foreman, J., and Nelson, Määttä, T., Tervo-Määttä, T., Taanila, A., Kaski, M., and Iivanainen, M. (2006). L. (2007c). Discourse skills of boys with fragile x syndrome in comparison Mental health, behaviour and intellectual abilities of people with Down to boys with down syndrome. J. Speech Lang. Hear. Res. 50, 475–492. syndrome. Down Synd. Res. Pract. 11, 37–43. doi: 10.3104/reports.313 doi: 10.1044/1092-4388(2007/033) Martin, G. E., Barstein, J., Hornickel, J., Matherly, S., Durante, G., and Losh, Roberts, J. E., Graham, F. P., Hennon, E. A., Price, J. R., Dear, E., Anderson, M. (2017). Signaling of noncomprehension in communication breakdowns K., et al. (2007a). Expressive Language during conversational speech in boys in fragile X syndrome, Down syndrome, and autism spectrum disorder. J. with fragile x syndrome. Am. J. Ment. Retard. 1, 1–17. doi: 10.1352/0895- Commun. Disord. 65, 22–34. doi: 10.1016/j.jcomdis.2017.01.003 8017%282007%29112%5b1:ELDCSI%5d2.0.CO;2

Frontiers in Genetics | www.frontiersin.org 14 October 2018 | Volume 9 | Article 424 del Hoyo Soriano et al. Phenotypic Comparison Between DS and FXS

Roberts, J. E., Price, J., and Malkin, C. (2007b). Language and communication Tannock, R. (1988). Mothers’ directiveness in their interactions with their children development in Down syndrome. Men. Retard. Dev. Disabil. Res. Rev. 13, with and without Down syndrome. Am. J. Mental Retard 93, 154–165. 26–35. doi: 10.1002/mrdd.20136 Thurman, A. J., Mcduffie, A., Hagerman, R., and Abbeduto, L. (2014). Roberts, J., Price, J., Barnes, E., Nelson, L., Burchinal, M., Hennon, E. A., Psychiatric symptoms in boys with fragile X syndrome: a comparison with et al. (2007d). Receptive vocabulary, expressive vocabulary, and speech nonsyndromic autism spectrum disorder. Res. Dev. Disabil. 35, 1072–1086. production of boys with fragile x syndrome in comparison to boys with doi: 10.1016/j.ridd.2014.01.032 down syndrome. Am. J. Ment. Retard. 177, 177–193. doi: 10.1352/0895- Tonge, B. J., and Einfeld, S. L. (2003). Psychopathology and intellectual disability: 8017(2007)112[177:RVEVAS]2.0.CO;2 the Australian child to adult longitudinal study. Int. Rev. Res. Ment. Retard. 26, Roid, G. H., and Miller, L. J. (1997). Leiter International Performance Scale-Revised. 61–91. doi: 10.1016/S0074-7750(03)01002-4 Wood Dale, IL: Stoelting. Turk, J. (1998). Fragile X syndrome and attentional deficits. J. Appl. Saldarriaga, W., Tassone, F., González-Teshima, L. Y., Forero-Forero, J. V., Ayala- Res. Intellect. Disabil. 11, 175–191. doi: 10.1111/j.1468-3148.1998.tb Zapata, S., and Hagerman, R. (2014). Fragile X syndrome. Colombia Medica 45, 00060.x 190–198. Van Gameren-Oosterom, H. B., Fekkes, M., Buitendijk, S. E., Mohangoo, A. D., Scattone, D., Raggio, D. J., and May, W. (2011). Comparison of the Bruil, J., Van Wouwe, J. P., et al. (2011). Development, problem behavior, vineland adaptive behavior scales, second edition, and the bayley scales of and quality of life in a population based sample of eight-year-old children infant and toddler development, third edition. Psychol. Rep. 109, 626–634. with down syndrome. PLoS ONE 6:e21879. doi: 10.1371/journal.pone.00 doi: 10.2466/03.10.PR0.109.5.626-634 21879 Shapiro, B. K., and Accardo, P. J. (2010). Neurogenetic Syndromes : Behavioral Van Gameren-Oosterom, H. B., Fekkes, M., Van Wouwe, J. P., Detmar, S. B., Issues and Their Treatment. Baltimore, MD: Paul H. Brookes Publishing Co. Oudesluys-Murphy, A. M., and Verkerk, P. H. (2013). Problem behavior of Smith, E., Næss, K. A. B., and Jarrold, C. (2017). Assessing pragmatic individuals with Down syndrome in a nationwide cohort assessed in late communication in children with Down syndrome. J. Commun. Disord. 68, adolescence. J. Pediatri. 163, 1396–1401. doi: 10.1016/j.jpeds.2013.06.054 10–23. doi: 10.1016/j.jcomdis.2017.06.003. Williams, K. (1997). Expressive Vocabulary Test. Circle Pines, MN: American Sterling, A., and Abbeduto, L. (2012). Language development in school- Service. age girls with fragile X syndrome. J. Intellect. Disabil. Res. 56, 974–983. Wolf-Schein, E. G., Sudhalter, V., Cohen, I. L., Fisch, G. S., Hanson, D., Pfadt, A. doi: 10.1111/j.1365-2788.2012.01578.x G., et al. (1987). Speech-language and the fragile X syndrome: initial findings. Stoel-Gammon, C. (2001). Down syndrome phonology: developmental ASHA 29, 35–38. patterns and intervention strategies. Down Synd. Res. Pract. 7, 93–100. doi: 10.3104/reviews.118 Conflict of Interest Statement: The authors declare that the research was Sudhalter, V., and Belser, R. C. (2001). Conversational characteristics of children conducted in the absence of any commercial or financial relationships that could with fragile X syndrome: tangential language. Am. J. Ment. Retard. 106, be construed as a potential conflict of interest. 389–400. doi: 10.1352/0895-8017(2001)106<0389:CCOCWF>2.0.CO;2 Sudhalter, V., Cohen, I. L., Silverman, W., and Wolf-Schein, E. G. (1990). Copyright © 2018 del Hoyo Soriano, Thurman and Abbeduto. This is an open-access Conversational analyses of males with fragile X, Down syndrome, and autism: article distributed under the terms of the Creative Commons Attribution License (CC comparison of the emergence of deviant language. Am. J. Mental Retard. 94, BY). The use, distribution or reproduction in other forums is permitted, provided 431–441. the original author(s) and the copyright owner(s) are credited and that the original Symons, F. J., Clark, R. D., Hatton, D. D., Skinner, M., and Bailey, D.B.(2003).Self- publication in this journal is cited, in accordance with accepted academic practice. injurious behavior in young boys with fragile X syndrome. Am. J. Med. Genet. No use, distribution or reproduction is permitted which does not comply with these 118A, 115–121. doi: 10.1002/ajmg.a.10078 terms.

Frontiers in Genetics | www.frontiersin.org 15 October 2018 | Volume 9 | Article 424